Abstract
The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.
Highlights
The erythropoietin-producing hepatocellular car cinoma (Eph) receptors constitute the largest family of receptor tyrosine kinases and are comprised of 14 different receptors and their cognate ligands, the ephrins [1, 3]
We evaluated the expression of EphB1 in a human medulloblastoma cell line, DAOY, and found EphB1 to be expressed at both the mRNA and protein level (Figure 1A, 1B)
We found that EphB1 mRNA levels were reduced to 18% or less by 24 h in the EphB1knockdown group compared to the control, non-specific Short interfering RNAs (siRNA) (Ns-siRNA) transfected group, with optimal knockdown efficiency observed at 72 h post-transfection (Figure 1A)
Summary
The erythropoietin-producing hepatocellular car cinoma (Eph) receptors constitute the largest family of receptor tyrosine kinases and are comprised of 14 different receptors and their cognate ligands, the ephrins [1, 3]. Members of the Eph/ ephrin families are known to fulfill important roles in tissue formation and organization including axon guidance, synaptogenesis and pattern formation [1]. Given their importance in normal development, it is not surprising that the deregulation of normal Eph/ephrin signaling is involved in tumorigenesis [2, 3], with recent reports focusing on the effects of Eph/ephrin system on cell adhesion, migration, proliferation, and angiogenesis [4, 5]. There are significant neurological, cognitive, endocrinological, and social sequelae resulting from current chemotherapy and radiotherapy regimens In light of this prognosis, significant efforts are underway to develop more effective and less toxic treatments for medulloblastoma patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
